Coronary heart disease (CHD) is the leading cause of death in humans in the U.S. CHD heart disease is so pervasive that more humans die of heart disease than from any other disease. CHD is caused by a narrowing of the coronary arteries that supply blood to the heart. This often results in a heart attack in the victim. Unfortunately, each year about a million Americans have a heart attack and tragically about half or more of these heart attacks are fatal before the heart attack victim can get to a hospital. Heart disease includes congestive heart failure and malignant ventricular arrhythmias. Electrophysiologic dysfunction is believed to be the major cause of death during myocardial infarction in humans8.
Several Research Publications suggest that activation of myocardial phospholipases during acute cardiac ischemia resulted in the generation of amphiphilic metabolites which alter ion channel function thereby precipitating lethal ventricular dysrhythmias1-3,9-11. Since myocytic electrophysiologic function is influenced by the physiochemical properties of the lipids surrounding ion channels12-13, accelerated hydrolysis of sarcolemmal phospholipid constituents during acute ischemia could potentially provide a foundation for understanding the biochemical basis of ischemia-induced arrhythmias. Additionally, myocardium contains at least three distinct intracellular phospholipase A2 activities encoded on discrete genes (iPLA2β, iPLA2γ, and cPLA2γ)14,15.
Without being bound by theory, in the early stage of CHD, it is believed that plaque or fatty materials build up inside the walls of human arteries (carrying oxygenated blood) along with blood components which are attracted to the plaque or fatty materials. Sometimes the fatty buildup or plaque breaks open in a human artery which leads to formation of a clot that seals the defect in the artery but unfortunately restricts blood flow. When too little blood reaches the heart, as a result of this restriction in blood flow, the medical condition ischemia or myocardial ischemia results.
In some situations when the ischemia is of a long duration there is generally a resulting heart attack which unfortunately is all too often sometimes fatal. In other situations ischemia disturbs the heart's rhythm inducing an abnormal increasingly disruptive rhythm such as malignant ventricular arrhythmia which is usually destructively fatal.
Arrhythmias include the ventricular and supraventricular type. In the ventricular type the arrhythmias occur in an area in the ventricles typically in or adjacent to the ischemic part. It is believed that arrhythmias in the left ventricle of the heart lead to the most common cause of death due to an ischemic episode from atherosclerosis. These are called ventricular arrhythmias and include ventricular tachycardia, ventricular fibrillation and premature ventricular contractions. Lasting durational ventricular arrhythmias termed malignant ventricular arrhythmia. Malignant ventricular arrhythmia is particularly fatal to humans.
In an effort to combat fatal human heart attacks, medical research strives to identify drugs which are effective against malignant ventricular arrhythmias. However, difficult challenges are presented to that effect in that the process of discovering and developing new pharmaceutical drugs is increasingly expensive and challenging. For example, the average length of time from the discovery of a candidate drug to the time of its US Federal Drug Administration approval has increased. And currently, it is estimated that an average of 10,000 or more lead compounds must be tested in pre-clinical development for every drug that is finally marketed.
Additionally it is estimated that existing pharmaceutical drugs interact with less than five hundred or so biological targets out of an estimated large number of potential targets (˜10,000). If this estimate is correct then, this means that the majority of potential drug targets remain undiscovered using presently available techniques.
Thus, despite rapid and noteworthy advances in medical science in this field, a dire need exists for a method of identifying pharmacological drugs which are therapeutic to preventing or ameliorating dangerous and potentially fatal (malignant) ventricular arrhythmias in humans.